The long term objective of this research proposal is to understand the cellular and molecular mechanisms of the cardiac lesions observed in HIV-1 transgenic mice that the applicants have recently constructed. In these mice, the HIV-1 gene products are expressed in cells which are the target of HIV-1 infection in humans, namely CD4+T cells and cells of the dendritic/macrophage lineage. The cardiac lesions are similar to those described in HIV-1-infected individuals. The investigators would like to understand the pathogenesis of these cardiac lesions and more specifically, intend; 1) To identify the HIV-1 gene product(s) responsible for this cardiac phenotype by constructing HIV-1 mutants; 2) To characterize changes in the pattern of gene expression in the heart of HIV-1 transgenic mice; 3) To identify the cells expression HIV-1 in the heart by in situ hybridization and immunocyto-chemistry; 4) To determine the contributions of each cell type (T lymphocytes and cells of the dendritic/macrophage lineage) to the development of cardiac lesions; 5) To determine whether the ablation of specific host genes (IL-6,TNF,R, iNOS, ICE) prevents the appearance of cardiac lesions; 6) To determine the role of monocytes/macrophages derived cytokines in cardiotoxicity using cocultures of normal of HIV-1 transgenic macrophages and cardiomyocytes; and 7) To determine whether apoptosis of cardiomyocytes is a major feature of cardiomyopathy observed in these mice. (End of Abstract)